PROJECT SUMMARY Systemic amyloid diseases are a class of disorders pathologically associated with the aggregation and deposition of destabilized, amyloidogenic proteins on peripheral target tissues distal from the site of protein synthesis such as the kidney, gut, heart, and peripheral nerves. Over 1 million individuals have been diagnosed with these deadly diseases, although this is likely a significant underestimate of disease prevalence as many undiagnosed renal and cardiac disorders are now being shown to involve systemic amyloid disease pathology. Destabilizing mutations in over 15 different proteins, the majority of which are synthesized in the liver, predispose individuals to systemic amyloid diseases. Since the pathology of these diseases is tightly linked to the site of deposition, systemic amyloid diseases have traditionally been viewed as disorders of the affected peripheral target tissues (e.g. renal disease, cardiomyopathy, and neuropathy). However, over the past 10 years, significant clinical and biological evidence has revealed a critical role for the liver in dictating the extracellular aggregation and deposition of amyloidogenic proteins. These results have challenged the traditional view of systemic amyloid diseases and indicate that these disorders may be best viewed as diseases of the liver. However, the mechanisms by which the liver contributes to systemic amyloid disease pathogenesis remain poorly defined. Here, we hypothesize that imbalances in liver endoplasmic reticulum (ER) protein homeostasis (or proteostasis) promotes the toxic extracellular aggregation of amyloidogenic proteins implicated in systemic amyloid disease pathogenesis. Significant published results from our groups strongly support a critical role for liver ER proteostasis in the toxic aggregation of liver-derived amyloidogenic proteins such as transthyretin (TTR). We showed that disrupting or enhancing ER proteostasis in cells secreting destabilized, amyloidogenic proteins such as TTR directly impacts their extracellular aggregation into toxic oligomers and amyloid fibrils implicated in systemic amyloid disease pathogenesis. Here, we will show that imbalances in liver ER proteostasis promotes the extracellular aggregation and peripheral toxicity of multiple amyloidogenic proteins. These results will demonstrate that diverse genetic, environmental, or aging-related factors that impact ER proteostasis in the liver can promote peripheral toxicity of multiple liver-synthesized amyloidogenic proteins, establishing a molecular framework to explain the clinical importance of the liver in the pathogenesis of these diseases. Furthermore, we will show that enhancing ER proteostasis in the liver through pharmacologic activation of endogenous unfolded protein response (UPR)-associated signaling pathways that regulate ER proteostasis offers a broadly-applicable strategy to ameliorate the secretion, extracellular aggregation, and peripheral toxicity of multiple amyloidogenic proteins. These results will establish pharmacologic UPR activation as a new therapeutic opportunity to treat this largely untreatable class of disease through a one drug:multiple disease therapeutic paradigm.